Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving virus or bacteriophage
Reexamination Certificate
2000-01-25
2001-07-31
Park, Hankyel T. (Department: 1648)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving virus or bacteriophage
C424S078050, C424S078270, C424S078350, C526S315000
Reexamination Certificate
active
06268126
ABSTRACT:
BACKGROUND OF THE INVENTION
One mechanism for infection of a host cell by a microbe, such as a virus, a bacterium or a protozoan, proceeds via initial attachment of the microbe to the host cell surface. This process is mediated by relatively weak attractive interactions between adhesion molecules on the surfaces of the microbe and the host cell. In general, microbe-host cell attachment is the product of a multiplicity of such interactions, via what has been referred to as the polyvalent effect. One well-studied example of such a process is the attachment of the influenza A virus to mammalian epithelial cells, which results from interaction of terminal N-acetylneuraminic acid groups of glycolipids and glycoproteins on the host cell surface with the attachment glycoprotein hemagglutinin on the viral surface.
The scarcity of effective antiviral agents points to the need for new approaches to the treatment of viral infections. The attachment step is an attractive target for such a treatment, and much activity has focused on the development of N-acetylneuraminic acid-containing compounds capable of binding to viral hemagglutinin, thus inhibiting viral attachment to host cells. Studies have demonstrated that polyvalent compounds, such as polymers bearing pendant N-acetylneuraminic acid groups, bind influenza virus with association constants which are several orders of magnitude higher than those of monomeric N-acetylneuraminic acid derivatives. To date, no polyvalent N-acetylneuraminic acid containing compounds are in clinical use for treatment or prevention of influenza. Moreover, no data demonstrating in vivo efficacy of such compounds have yet been published.
A disadvantage of N-acetylneuraminic acid-functionalized compounds as therapeutic agents for the treatment of infection by influenza A virus and, possibly, other viruses, is the great expense of this sugar. In addition, the influenza virus has at its surface the enzyme neuramidinase, which cleaves N-acetylneuraminic acid moieties from such molecules, eventually destroying their ability to bind the virus. There is, thus, a need for inhibitors of viral attachment to mammalian cells which have an improved efficacy, are readily prepared from inexpensive starting materials and have a broad spectrum of activity.
SUMMARY OF THE INVENTION
The present invention relates to a method of treating a viral infection in an animal, such as a human, by administering to the animal a therapeutically effective amount of a polymer having a plurality of pendant hydrophobic groups and pendant acid functional groups which are directly attached to the polymer backbone or attached to the polymer backbone by an aliphatic spacer group. The aliphatic spacer group can have a length in the range from 1 to about 20 atoms.
Suitable acid functional groups include carboxylic acid, sulfonic acid, phosphonic acid, hydrosulfate and boronic acid groups. The acid groups can also be present in the conjugate base form. Suitable hydrophobic groups include normal or branched C
2
-C
20
-alkyl groups, arylalkyl groups and aryl groups.
In one embodiment, the polymer to be administered comprises a monomer or repeat unit having an acid functional group and a hydrophobic group. In another embodiment, the polymer is a copolymer comprising an acid-functionalized monomer and a hydrophobic monomer. The polymer to be administered can, optionally, further include a monomer comprising a neutral hydrophilic group, such as a hydroxyl group or an amide group.
The present method has several advantages. For example, the polymers employed are easily prepared using standard techniques of polymer synthesis and inexpensive starting materials. The polymers will not be substantially degraded in the gastrointestinal tract and, therefore, can be administered orally. Polymer compositions can also be readily varied, to optimize properties such as solubility or water swellability and antiviral activity. Finally, the polymers to be administered include acid functional groups attached to the polymer backbone via aliphatic spacer groups. The structural flexibility of such spacer groups minimizes backbone constraints on the interaction of the acid groups with viral targets.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a method of treating a viral infection in an animal, such as a human, by administering to the animal a therapeutically effective amount of a polymer comprising a plurality of pendant acid functional groups and pendant hydrophobic groups. The acid functional group can be directly bonded to the polymer backbone or separated from the polymer backbone by an aliphatic spacer group having a length of from 1 to about 20 atoms.
The polymer can be administered in the acid form, in which all acidic groups are protonated or in the conjugate base form, wherein the acidic functional groups are deprotonated and carry a negative charge. In the conjugate base form the negative charge of the polymer will be balanced by a suitable number of counter cations, such as alkali metal ions, for example, sodium, potassium or cesium ions, alkaline earth metal ions, such as magnesium ions, or tetraalkylammonium ions. The polymer can also be administered in a partially deprotonated form, in which the extent of deprotonation is less than 100%.
As used herein, a “therapeutically effective amount” is an amount sufficient to inhibit or prevent, partially or totally, a viral infection or to reverse the development of a viral infection or prevent or reduce its further progression.
The term “monomer”, as used herein, refers to both a molecule comprising one or more polymerizable functional groups prior to polymerization, and a repeating unit of a polymer. A copolymer is said to comprise two or more different monomers.
As used herein, the term “polymer backbone” or “backbone” refers to that portion of the polymer which is a continuous chain, comprising the bonds which are formed between monomers upon polymerization. The composition of the polymer backbone can be described in terms of the identity of the monomers from which it is formed, without regard to the composition of branches, or side chains, off of the polymer backbone. Thus, poly(acrylic acid) is said to have a substituted poly(ethylene) backbone with carboxylic acid (—C(O)OH) groups as side chains.
A “pendant” group is a moiety which forms a side chain or a portion of a side chain attached to the polymer backbone.
The acid-functionalized monomer comprises a pendant acid functional group, such as a carboxylic acid group, a sulfonic acid group, a hydrosulfate group, a phosphonic acid group, a boronic acid group. The acid functional group can also be present in the anionic, or conjugate base, form, in combination with a cation. Suitable cations include alkaline earth metal ions, such as sodium and potassium ions, alkaline earth ions, such as calcium and magnesium ions, and unsubstituted and substituted (primary, secondary, tertiary and quaternary) ammonium ions.
The aliphatic spacer group is a component of the polymer side chain and connects the acid functional group to the polymer backbone. The term “aliphatic” describes a chemical moiety which is not aromatic and does not comprise an aromatic component. The spacer group can be linear, branched or cyclic. Suitable aliphatic spacer groups include normal or branched, saturated or partially unsaturated hydrocarbyl groups, including alkylene groups, for example, polymethylene groups such as —(CH
2
)
n
—, wherein n is an integer from 1 to about 20, and cycloalkylene groups, such as the 1,4-cyclohexylene group. The alkylene group can be substituted or unsubstituted. Suitable alkylene substituents include hydroxyl groups and halogen atoms, for example, fluorine, chlorine and bromine atoms. The alkylene group can also, optionally, be interrupted at one or more points by a heteroatom, such as an oxygen, nitrogen or sulfur atom. Examples include the oxaalkylene groups —(CH
2
)
2
O[(CH
2
)
2
O]
n
(CH
2
)
2
—, wherein n is an integer ranging from 0 to about 3. The aliphatic spacer group can a
Mandeville, III W. Harry
Neenan Thomas X.
GelTex Pharmaceuticals Inc.
Hamilton Brook Smith & Reynolds P.C.
Park Hankyel T.
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